The enzyme tyrosine kinase Bcr-Abl-1 is the main molecular target in the treatment of chronic myeloid leukemia and can be competitively inhibited by tyrosine kinase inhibitors such as imatinib. New potential competitive inhibitors were synthesized using the phenylamino pyrimidine pyridine (PAPP) group as a pharmacophoric fragment, and these compounds were biologically evaluated. The synthesis of the twelve new compounds was performed in three steps and assisted by microwave irradiation in a 1,3-dipolar cycloaddition to obtain 1,2,3-triazole derivatives substituted on carbon C-4 of the triazole nucleus. All of them had their inhibitory activities evaluated against a chronic myeloid leukemia cell line (K562) that expresses the enzyme tyrosine kinase Bcr-Abl-1 and against healthy cells (WSS-1) to observe their selectivity. Three compounds had promising results, showing an IC50 between 1.0 and 7.3 mM, and were subjected to molecular docking studies. This result suggests that such compounds can interact at the same binding site as imatinib, probably sharing a competitive inhibition mechanism. One of them showed the greatest interaction affinity for Bcr-Abl-1 in the docking studies.
Keywords: chronic myeloid leukemia; 1,3-dipolar cycloaddition; imatinib; phenylamino pyrimidine pyridine; 1,2,3-triazole.
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Pimentel, L. C. F.; Hoelz, L. V. B.; Canzian, H. F.; Branco, F. S. C.; de Oliveira, A. P.; Campos, V. R.; Júnior, F. P. S.; Dantas, R. F.; Resende, J. A. L. C.; Cunha, A. C.; Boechat, N.; Bastos, M. M. Beilstein Arch. 2021, 202144. doi:10.3762/bxiv.2021.44.v1
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